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Editors Selection IGR 17-4

Basic Research: Brn3a and RGC survival

Comment by Adriana DiPolo on:

24127 Brn3a as a marker of retinal ganglion cells: qualitative and quantitative time course studies in naive and optic nerve-injured retinas, Nadal-Nicolás FM; Jiménez-López M; Sobrado-Calvo P et al., Investigative Ophthalmology and Visual Science, 2009; 50: 3860-3868

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The irreversible loss of retinal ganglion cells (RGCs) is the primary cause of visual impairment in all optic neuropathies, including glaucoma. Techniques that allow the selective identification of these neurons are essential for studies on neurodegeneration and neuroprotection after optic nerve injury. The gold standard for labeling rodent RGCs is the application of fluorescent retrograde tracers (e.g., Fluorogold, DiI) to their main target in the brain, the superior colliculus. The availability of novel methods to selectively identify RGCs using standard procedures, such as immunohistochemistry or in situ hybridization, would provide a useful and complementary approach to investigate the response of injured RGCs. In their recent study, Nadal-Nicolás et al. (1019) convincingly demonstrate that Brn3a, a member of the Brn3 family of POU-domain transcription factors, is a reliable immunocytochemical marker for adult rat RGCs.

Brn3a is a reliable immunocytochemical marker for adult rat RGCs

The authors found an excellent correlation between Brn3a-positive and Fluorogold-positive cells (92%), confirming that most RGCs express Brn3a, while only ~5% of Brn3a-positive cells were not labeled with Fluorogold and may account for a sub-population of displaced amacrine cells that express Brn3a. The pattern of Brn3a immunoreactivity was also examined after optic nerve transection or crush and, importantly, Brn3a remained restricted to cells in the ganglion cell layer in these injury paradigms. The temporal loss of Brn3a immunoreactivity, however, occurred much earlier than the loss of Fluorogold in injured RGCs.

Early Brn3a expression downregulation may lead to underestimation of the actual number of RGCs that remain after lesion and, consequently, neurons that are potentially amenable to neuroprotective treatments may be overlooked

For example, at five days after optic nerve transection there were ~69,000 Fluorogold-positive RGCs while only ~29,500 Brn3a-positive cells were detected. These results raise a potential imitation of this and other approaches based on the use of markers susceptible to injury-induced changes in gene expression. Early Brn3a expression downregulation may lead to underestimation of the actual number of RGCs that remain after lesion and, consequently, neurons that are potentially amenable to neuroprotective treatments may be overlooked. The authors suggest that the early loss of Brn3a expression reflects a commitment of the cell to die, hence preceding the disappearance of Fluorogold. This is an interesting hypothesis that needs to be experimentally tested to precisely assess the correlation between Brn3a and RGC survival following acute optic nerve injury. In summary, this is an important and useful study that identifies Brn3a as a reliable and efficient ex vivo marker for intact and injured RGCs.

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